6-cyano-4,6-pregnadienes,methods for their manufacture,and intermediates thereof

ABSTRACT

6-CYANO-4,6-PREGNADIENE-3,20-DIONES HAVING PROGESTATIONAL ACTIVITY ARE PREPARED FROM 6-OXIMINOMETHYL-4,6PREGNADIENE-3,20-DIONES BY TREATMENT THEREOF WITH A DEHYDRATING AGENT SELECTED FROM THE GROUP CONSISTING OF PHOSPHORUS OXYCHLORIDE, A LOWER ALKANOIC ACID ANHYDRIDE IN PYRIDINE, AND A LOWER ALKANOIC ACID ANHYDRIDE IN THE PRESENCE OF SODIUM ACETATE. PREFERRED COMPOUNDS ARE 6CYANO-16-METHYLENE-17A-LOWER ALKANOYLOXY-4,6-PREGNADIENE-3,20-DIONES.

United States Patent 3,707,487 6-CYANO-4,6-PREGNADIENES, METHODS FORTHEIR MANUFACTURE, AND INTERMEDI- ATES THEREOF Thomas L. Popper, Verona,Hershel L. Herzog, Glen Ridge, and Elliot L. Shapiro, Cedar Grove,N..l., assignors to Schering Corporation, Bloomfield, NJ. No Drawing.Filed Jan. 28, 1971, Ser. No. 110,742 Int. Cl. C07c 169/34 US. Cl.260-3914 8 Claims ABSTRACT OF THE DISCLOSURE6-cyano-4,6-pregnadiene-3,ZO-diones having progestational activity areprepared from 6-oximinomethyl-4,6- pregnadiene-3,20-diones by treatmentthereof with a dehydrating agent selected from the group consisting ofphosphorus oxychloride, a lower alkanoic acid anhydride in pyridine, anda lower alkanoic acid anhydride in the presence of sodium acetate.Preferred compounds are 6- cyano-l6-methylene-l7wlower alkanoyloxy-4,6pregnadiene-3,20-diones.

FIELD OF INVENTION This invention relates to novelcompositions-of-matter, to methods for their manufacture, and to novelintermediates thereof.

More specifically, this invention relates to2l-unsubstituted-6-cyano-4,6-pregnadiene-3,20 diones havingprogestational activity, to methods for their manufacture and to novel21-unsubstituted-6-oximinomethyl-4,6-pregnadiene-3,20-dioneintermediates useful therein.

DESCRIPTION OF PRIOR ART Known in the art are 3-enol ethers of6-oximinomethyl progesterones (i.e., 3-lower alkoxy-6-oximinomethyl-3,5-pregnadien-ZO-ones) and the process of treating a 3-enol ether of a6-oximinomethylprogesterone with a lower alkanoic acid anhydride,preferably in the presence of an alkali metal acetate, to form a 3-enolether of a 6-cyanoprogesterone (i.e., a 3-lowcralkoxy-6-cyano-3,5-pregnadien-ZO-one Also known in the art are 3-enolesters of 6-cyanoprogesterones (i.e., 3-lower alkanoxyloxy-6-cyano 3,5-pregnadien-ZO-ones) which when subjected to mild alkaline hydrolysis areconverted to an inseparable mixture of a 6-cyanoprogesterone and itsenol form, with the enol form predominating (i.e., a mixture of a6-cyano-4-pregnene-3, 20-dione and the corresponding enol,6-cyano-3,5-pregnadien-3-ol-20-one). Accordingly, unknown in the art isa 6- cyanoprogesterone free from its enol form.

By our invention, we have discovered that by treating an enol ether of a6-oximinomethylprogesterone with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (hereinafter referred to as DDQ)there is obtained a novel compound, i.e., a6-oximinomethyl-6-dehydroprogesterone, which, upon treatment with adehydrating agent selected from the group consisting of phosphorusoxychloride, a lower alkanoic acid anhydride in pyridine, and a loweralkanoic acid anhydride in the presence of sodium acetate, will producenovel compounds having progestational activity, i.e., 6-cyano-fi-dehydroprogesterones (also named 6-cyano-4,6-

Patented Dec. 26, 1972 pregnadiene-3,20-diones) wherein the carbonylgroup at C-3 exists only in the ketonic form.

SUMMARY OF INVENTION This invention to chemical compounds havingprogestational activity which have a molecular structure comprising a4,6-pregnadiene-3,20-dione nucleus with a cyano group at C6 andpreferably also having a methylene group at C16 and an alpha loweralkanoyloxy group at C-l7. Also included are 16-methyl derivatives andcompounds unsubstituted at both 0-16 and C-17.

The invention sought to be patented in a compositionof-matter aspectresides in the concept of a chemical compound useful as an intermediatewhich has a molecular structure comprising a 4,6-pregnadiene-3,20-dionenucleus with a 6-oximinomethyl group at C-6 and which may also besubstituted at C-l7 by an alpha lower alkanoyloxy group and at 0-16 bygroups such as methylene or methyl.

The invention sought to be patented in the process aspect of thisinvention resides in the concept of treating a 6-oximinomethyl-4,6-pregnadiene-3,ZO-dione with a dehydrating agentselected from the group consisting of phosphorus oxychloride, a loweralkanoic acid anhydride in pyridine, and a lower alkanoic acid anhydridein the presence of sodium acetate, whereby is produced a 6-cyano-4,6-pregnadiene-3,20-dione having progestational activity.

GENERAL DESCRIPTION OF THE INVENTION Composition-of-rnatter aspectIncluded among the physical embodiments of progestationally activecompositions-of-matter of this invention are 6-cyano-4,6-pregnadieneshaving the following structural Formula I:

wherein W is a member selected from the group consisting of hydrogen,methylene, (H t-methyl) and (Hp-methyl); and Y is a member selected fromthe group consisting of lower alkanoyloxy, and hydrogen when W ishydrogen or (H,methyl).

The lower alkanoyloxy groups are preferably derived from lower alkanoicacids having up to 8 carbon atoms including acetic, propionic,n-butyric, iso-butyric, trimethylacetic, valeric, iso-valeric, caproic,and capyrylic acids.

Preferred compuonds of this invention are those wherein W is methyleneand Y is lower alkanoyloxy, preferably acetoxy. Included among the17a-lower alkanoyloxy compounds of this invention are:

6-cyano-17a-acetoxy-4,6-pregnadiene-3,20-dione and the 16a-methyland16/3-metl1yl homologs thereof,

6-cyano-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-

dione (a preferred compound of this invention),

3 6-cyano-1'6-methylene-17a-propionyloxy-4,6-pregnadiene- 3,20-dione,6-cyano-l6-methylene-l7a-valeryloxy-4,6-pregnadiene- 3,20-dione, and'6-cyano-16-methylene-17u-caproyloxy-4,6-pregnadiene- 3,20-dione.

The compounds of 'Formula I of this invention also include compoundsunsubstituted at C-17 such as 6-cyano-4,6-pregnadiene-3,20-dione (i.e.6-cyano-6-dehydro progesterone),6-cyano-16a-methyl-4,6-pregnadiene-3,ZO-dione, and6-cyano-l6p-methyl-4,6-pregnadiene-3,20-dione.

The physical embodiment of the 6-cyano-6-dehydroprogesterones of FormulaI are characterized by being crystalline solids, usually off-white towhite in color, which are insoluble in water and soluble in most organicsolvents, although of limited solubility in dialkyl ethers and aliphatichydrocarbons.

The 6-cyano-6-dehydroprogesterones defined by Formula I prossessprogestational activity as demonstrated by studies in immature rats bythe well known Clauberg method via the intra-muscular route. Thecompounds may be used as medicaments in conditions requiring aprogestational agent, e.g. in fertility control and in the management ofvarious menstrual disorders. They may be administered via theintramuscular route in a manner similar to that in which knownprogestational agents, e.g., progesterone, are administered, the dosagedepending on the age and size of patient and in the nature and severityof the ailment being treated. The preferred 6-cyano-16-methylene-17a-lower alkanoyloxy-4,6-pregnadiene 3,20- diones possessenhanced progestational activity over that of the prior art enol-etherderivative of the corresponding 6,7-dihydro analog. Thus, for example,6-cyano-16-methylene-I7ct-acet0xy-4,6-pregnadiene-3,20-dione (preferredcompound of Formula I) exhibits about three times more progestationalactivity than the prior art 3-ethoxy-6-cyano-16-methylene-17u-acetoxy3,5 pregnadiene-3,20- dione (i.e., the 3-enol ethyl ether of6-cyano-16-methylene- 17a-acetoxyprogesterone) when tested in immaturerats via the intramuscular route by the Clauberg method.

The physical embodiments of the compounds of this invention which areuseful as intermediates include 6-oximino-methyl-6-dehydroprogesteronesof following structural Formula II:

wherein R is a member selected from the group consisting of hydrogen andlower alkanoyl; W is a member selected from the group consisting ofhydrogen, methylene, (H,a-methyl) and (Hp-methyl); and Y is a memberselected from the group consisting of lower alkanoyloxy, and hydrogenwhen W is hydrogen or (H,methyl).

The compounds defined by Formula II are useful as intermediates in theprocess aspect of our invention as described in detail hereinbelow; thepreferred compounds being 6-oximino-methyl-16-methylene-17a-loweralkanoyloxy (particularly 17a-acetoxy)-4,6-pregnadiene-3,20-diones sincethey are intermediates in preparing the preferred, progestationallyactive 6-cyano-16-methylene-l7alowera1kanoyloxy-4,6-pregnadiene-3,20-diones of Formula I.

Illustrative of compounds of Formula II are l7-unsubstituted compoundssuch as:

6-oximinomethyl-4,6-pregnadiene-3,20-dione and the 160:-

methyl and l6/3-mehyl homologs thereof,6-acetoximinoethyl-4,6-pregnadiene-3,20-dione and the 16a-methyl andloo-methyl homologs thereof, and 17a-l0wer alkanoyloxy derivatives suchas: 6-oximinomethyl-l7a-acetoxy-4,6-pregnadiene-3,20-dione and theIda-methyl and 16fl-methyl homologs thereof, 6-oximinomethyl-16-methylene- 17 ot-acetoxy-4,6-pregnadiene-3,20-dione,6-acetoximinomethyl-l-methylene-17a-acet0xy-4,6-pregnadiene-3,20-dione,6-oximinomethyl-l6-methylene-l7a-propionyloxy-4,6-

pregnadiene-3,20-dione,6-oximinomethyl-l6-methylene-17u-valeryloxy-4,6-pregnadiene-3,20-dione,and6-oximinomethyl-1d-methylene-l7u-caproyloxy-4,6-pregnadiene-3,20-di0ne.

The physical embodiments of the compounds defined by Formula II arecharacterized by being crystalline solids, usually white to off-white incolor, and soluble in chlorinated hydrocarbons, acetone, and lower alkylalcohols, e.g. methanol.

The 6-oximinomethyl-4,6-pregnadiene-3,20-dione of Formula II areconveniently derived from the known enol ether derivatives of thecorresponding 6,7-dihydro-analogs of Formula II which when treated withDDQ in aqueous actone (preferably acetone) utilizing techniques known inthe art convert rapidly in good yields to the6-oximinomethyl-4,6-pregnadiene-3,20-diones of Formula II. Thus, forexample, 3-ethoxy-6-oximinomethyl- 16-methylene-17a-acetoxy-3,S-regnadien-ZO-one treated with DDQ in 95% aqueous acetone at 20 C. for 45minutes is converted to6-oximinomethyl-16-methylenel7a-acetoxy-4,6-pregnadiene-3,20-dione whichis isolated in excellent yields utilizing chromatographic andcrystallization techniques.

It is surprising that the above described process produces 6oximinomethyl-4,6-pregnadiene-3,20-dione since we have found that thecorresponding 6-cyano-enol ethers, i.e. a 3alkoxy-6-cyano-3,S-pregnadiene-3,20-dione, are completely inert to DDQand even under forcing conditions (large excess of DDQ in refluxingdioxane for 48 hours) fail to produce the oxidized product, i.e., a6-cyano- 4,6 pregnadiene-3,20-dione. Indeed, we have also found that theforegoing reaction does not proceed with the use of other knowndehydrogenating agents such as chloranil.

Those compounds of Formula II wherein R is lower alkanoyl are derivedfrom the corresponding 6-oximinomethyl derivatives utilizing standardesterification techniques under basic conditions such as that utilizingan acid anhydride in pyridine. Thus, treatment of the aforedescribed 6oximinomethyl-l6-methylene-17a-acetoxy-4, 6 pregnadiene-3,20-dione (acompound of Formula II wherein R is hydrogen) with acetic anhydride inpyridine at 20 C. yields 6-acetoximinornethyl-16-methylene-17aacetoxy4,6-pregnadiene-3,20-dione (compound of Formula II wherein R is acetyl).

The 6-oximinomethylprogesterone enol-ether necessary precursors (i.e., 3ethoxy-d-oximinomethyl-3,5-pregnadien 20 ones of the6-oximinomethyl-6-dehydroprogesterones of Formula II are convenientlyprepared from the corresponding 6-formyl derivative according to knownprocedures by reaction with hydroxylamine hydrochloride in sodiumacetate. In turn, the 6-formyl enol ethers (e.g., 3ethoxy-6-formyl-16-rnethylene-17a-acetoxy-3,5-pregnadien-20-one) arederived from the corresponding 6-unsubstituted compounds (e.g.,3-ethoxy-l6-methylene-17uacetoxy 3,5-pregnadien-20-one) by reaction withphosphorus oxychloride in dimethylformamide followed by treatment withsodium acetate.

Process aspect of the invention The process aspect of this inventionprovides a method for preparing the pharmacologically active6-cyano-4,6- pregnadiene-3,20-diones of Formula I and resides in theconcept of treating a corresponding 6-oximinomethyl-4,6-pregnadiene-3,20-dione of Formula II with a dehydrating agent selectedfrom the group consisting of phosphorus oxychloride, a lower alkanoicacid anhydride in pyridine, and a lower alkanoic acid anhydride in thepresence of sodium acetate.

When phosphorus oxychloride is used as the dehydrating agent, theprocess of this invention is usually carried out by suspending 0rdissolving a 6-oximinomethyl-4,6- pregnadiene-3,20-dione (e.g.,6-oximinomethyl-16-methylene-17wacetoxy-4,6-pregnadiene-3,20-dione) in atertiary amine (preferably pyridine), adding an excess (usually a largeexcess) of phosphorous oxychloride per mole of 6- oximinopregnadiene,and stirring the reaction mixture, preferably under an inert atmosphere(e.g., nitrogen) at temperatures in the range of from about 0 C. toabout 40 C. (preferably at ambient temperatures) for about two hours, oruntil a thin layer chromatogram of an aliquot of the reaction mixtureindicates an absence of 6- oximinomethyl pregnadiene starting compound.The resulting 6-cyano-4,6-pregnadiene-3,20-dione (e.g., 6-cyano- 16methylene 17a-acetoxy-4,6-pregnadiene-3,20-dione) is then easilyisolated by addition of water, collection of the precipitate byfiltration or extraction, and purification using known methods such ascrystallization or via chromatographic techniques.

When a lower alkanoic acid anhydride either in pyridine or in thepresence of sodium acetate is used as a dehydrating agent, the6-oximinomethyl-4,6-pregnadiene- 3,20-dione (e.g.,6-oximinomethyl-16-methy1-17a-acetoxy- 4,6-pregnadiene-3,20-dione)together with a large molar excess of a lower alkanoic acid anhydride(usually acetic anhydride) either in pyridine or in the presence of acatalytic quantity of sodium acetate is usually heated at refluxtemperature for about two to three hours. Isolation of the resulting6-cyano-4,6pregnadiene-3,20-dione (e.g., 6 cyano16-methylene-17a-acetoxy-4,6-pregnadiene-3, 20-dione) is effected insimilar manner as when phosphorus oxychloride is used as dehydratingagent.

When a lower alkanoic acid anhydride either in pyriing agent employed inour process, it is preferable to use the anhydride of the same acid fromwhence is derived the lower alkanoate ester at C-17.

When utilizing a lower alkanoic anhydride in pyridine dehydrating agent(e.g., acetic anhydride in pyridine) the 6-oximinomethyl 4,6pregnadiene-3,20-dione (e.g., 6- oximinomethyl 16methylene-17u-acetoxy-4,6-pregnadiene-3,20-dione) is first converted toa 6-acyloximinomethyl 4,6 pregnadiene 3,20-dione intermediate (e.g., 6acetoximino 16 methylene-17a-acetoxy-4,6-pregnadiene 3,20-dione) whichcan be isolated and purified according to known procedures prior toconversion to the 6 cyano-4,6-pregnadiene-3,20-dione. In such cases, theesterification stage of the process is preferably carried out at ambienttemperatures. Thus, for example, when 6-oximinomethyl 16methylene-17ot-acetoxy-4,6-pregnadiene- 3,20-dione upon treatment withan excess of acetic anhydride in pyridine at about 20 C. for three days(or until the absence of the 6-oximinomethyl group is indicated by thinlayer chromatography), there is formed 6-acetoximino 16methylene-17u-acetoxy-4,6-pregnadiene-3,20- dione which, after isolationand purification, can then be further treated with a molar quantity ofacetic anhydride in pyridine at reflux temperature for about two hoursto yield the progestationally active 6-cyano derivative, 6- cyano 16methylene-17a-acetoxy-4,6-pregnadiene-3,20- dione.

Phosphorus oxychloride is the preferred dehydrating agent for carryingout our process. With phosphorus oxychloride, the dehydration reactionproceeds faster and at lower temperatures and produces greater yields ofpurer 6-cyano-4,6-pregnadiene-3,20-dione product than when utilizing alower alkanoic acid anhydride dehydrating agent.

Our invention is further described in the examples which follow. Theseexamples are set forth by way of illustration only. It will beunderstood the invention is not to be construed as limited in scope bythe details set forth therein, since modifications and equivalents bothin materials and methods will be apparent from the disclosure to thoseskilled in the art.

EXAMPLE 1 6-oximinomethyl-1'6-methylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione methanol AIDA.

(B) 3ethoxy-6-oximinomethyl-16-methylene-17a-acetoxy-3,S-pregnadiene-20-one.--Add186 mg. sodium ace tate to a solution of 500 mg. of3-ethoxy-6-formyl-16- methylene-17a-acetoxy-3,S-pregnadien-ZO-one and 88mg. of hydroxylamine hydrochloride in 10 ml. ethanol and 2 ml. of water.Heat the reaction mixture at reflux temperature for 30 minutes, thenpour into water. Collect by filtration and air dry the resultantprecipitate comprising3-ethoxy-6-oximinomethyl-16-methylene-17a-acetoxy-3,S-pregnadien-ZO-one.Purify by chromatographing over deactivated silica gel (15% water, 57 x2 cm.) eluting with benzene-ether (9:1). Evaporate the benzene-ethereluates and recrystallize the resultant residue from ethanol-water toyield 324 mg. (63%) of3-ethoxy-6-oximinomethyl-16-methylene-17a-acetoxy-3,5 pregnadien-ZO-oneas a hemihydrate; M.P., 135-140 C.; [a] 151 (chloroform) xggi j 296 mg21,000)

(C) 6 oximinomethyl-16-methylene-17x-acetoxy-4,6pregnadiene-3,20-dione.-To a solution of 3.48 g. of 3-ethoxy-6-oximinomethy1 16 methylene-17a-acetoxy-3,5-pregnadiene-3,20-dione in ml. of aqueous acetone, add 3 g. ofdichlorodicyanobenzoquinone (DDQ) and stir the reaction mixture at 20 C.for 45 minutes. Pour the reaction mixture onto a column of neutralalumina (Woelm, activity grade I) and elute with chloro form in ethanol(1:1). Evaporate the combined eluates and rechromatograph the resultantresidue over neutral alumina (Woelm, activity grade I). Elute withchloroform. Evaporate the chloroform eluate to a residue comprising 6oximinomethyl-l6-methylene-17a-acetoxy-4,6- pregnadiene-3,20-dione.(Yield, 2.21 g.) Purify by crystallization from ethyl acetate to givethe ethyl acetate solvate of6-oximinomethyl-16-methylene-17u-acetoxy-4,6- pregnadiene-3,20-dione;M.P., -145 C.; [0:] -103 (dioxane);

Amethanol max.

7 EXAMPLE 2 6 cyano-1 rnethylene-17ot-acetoxy-4,6-pregnadiene-3,20-dione 6-cyano-16-methylene-17a-acetoxy-6-dehydroprogesterone) (A) To asolution of 488 mg. of -oxyminomethyl-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione in ml. of pyridine,add 2.2 ml. of phosphorus oxychloride and stir the reaction mixture fortwo hours at room temperature under an atmosphere of nitrogen. Pour thereaction mixture into water, collect by filtration the resultantprecipitate comprising 6-cyano-16-methylene-17ot-acetoxy-4,6-pregnadiene-3,ZO-dione. Air dry the foregoing precipitate and purifyby crystallization from ethyl acetate to give 329 mg. (70%) of6-cyano-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione; M.P.,221-223" C.; ]1)

Alternatively, the compound of this example is prepared according tofollowing procedures B and C.

(B) 6 Acetoximinomethyl-l6-methylene-l7a-acetoxy-4,6-pregnadiene-3,20-dione.-To a solution of 1.1 g. of 6oximinomethyl-16-methylene-17ot-acetoxy-4,6-pregnadiene-3,20-dione inml. pyridine, add 5 ml. acetic anhydride and allow the reaction mixtureto stand at C. for three days. Add the reaction mixture to water, thencollect by filtration and air dry the resultant precipitate comprising6-acetoximinomethyl-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione; yield, 1.106 g.; M.P., 120-126"C.;

6-cyano-17a-acetoxy-4,6-pregnadiene-3,20-dione (A)6-oximinomethyl-17a-acetoxy 4,6 pregnadiene- 3,20-dione.-In a mannersimilar to that described in Example lC, treat3-methoxy-6-oximinomethyl-17a-acetoxy- 3,5-pregnadien-20-one in 95%aqueous acetone with dichlorodicyanobenzoquinone at 20 C. for minutes.Isolate and purify the resultant product in a manner similar to thatdescribed in Example 1C to obtain6-oximinomethyl-17a-acetoxy-4,6-pregnadiene-3,20-dione.

(B) 6-cyano-17a-acetoxy-4,6-pregnadiene-3,20-dione.--

In a manner similar to that described in Example 2A,

' treat 6-oximinomethyl-17u-acetoxy-4,6-pregnadiene-3,20-

dione with phosphorus oxychloride in pyridine at 20 C. under anatmosphere of nitrogen. Isolate and purify the resultant product in amanner similar to that described in Example 2A to obtain6-oximinomethyl-l7ot-acetoxy- 4,6-pregnadiene-3,20-dione.

EXAMPLE 4 6-cyano-4,6-pregnadiene-3,20-dione (A) 3 ethoxy 6 tormyl 3,5pregnadien 20- one.--In a manner similar to that described in Example1A, treat 3-ethoxy-3,S-pregnadien-ZO-one with a solution of phosphorusoxychloride in dimethylformamide followed by treatment of the reactionmixture with aqueous potassium acetate. Isolate and purify the resultant8 product in a manner similar to that described in Example 1A to obtain3-ethoxy-6-formyl-3,S-pregnadien-ZO-one.

(B) 3-ethoxy 6 oximinomethyl-3,5-pregnadien-20- one.In a manner similarto that described in Example 1B, treat3-ethoxy-6-formyl-3,5-pregnadien-20-one with hydroxylamine hydrochloridein aqueous ethanol to gether with sodium acetate. Isolate and purify theresultant product in a manner similar to that described in Example 1B toobtain 3-ethoxy-6-oximinomethyl-3,5- pregnadien-ZO-one.

(C) 6 oximinomethyl 4,6 pregnadiene 3,20- dione.In a manner similar tothat described in Example 1C, treat 3 ethoxy 6 oximinomethyl 3,5pregnadien- 20-one with dichlorodicyanobenzoquinone in aqueous acetoneat 20 C. Isolate and purify the resultant product in a manner similar tothat described in Example 1C to obtain6-oximinomethyl-4,6-pregnadiene-3,20-dione.

(D) 6-cyano-4,6-pregnadiene-3,20-dione.-In a manner similar to thatdescribed in Example 2A, treat6-oximinomethyl-4,6-pregnadiene-3,20-dione with phosphorus oxychloridein pyridine under an atmosphere of nitrogen at 20 C. Isolate and purifythe resultant product in a manner similar to that described in Example2A to obtain 6-cyano-4,6-pregnadiene-3,20-dione.

Alternatively, the compound of this example is prepared from6-oximinomethyl-4,6-pregnadiene-3,20-dione according to followingprocedures E and F.

(E) 6 acetoximinomethyl 4,6 pregnadiene 3,20- dione.--In a mannersimilar to that described in Example 2B, treat 6 oximinomethyl 4,6pregnadiene 3,20- dione with acetic anhydride in pyridine at 20 C.Isolate and purify the resultant product in a manner similar to thatdescribed in Example 2B to obtain6-acetoximinomethyl-4,6-pregnadiene-3,20-dione.

(F) 6-cyano-4,6-pregnadiene-3,20-dione.-In a manner similar to thatdescribed in Example 2C, treat 6-acetoximinomethyl 4,6 pregnadiene 3,20dione with acetic anhydride in pyridine at reflux temperature for twohours. Isolate and purify the resultant product in a manner similar tothat described in Example 2C to obtain6-cyano-4,6-pregnadiene-3,20-dione.

EXAMPLE 5 Other 6-cyano-4,6-pregnadiene-3,20-diones (A) 3 ethoxy 6formyl 3,5 pregnadien 20- ones.--The requisite enol-ether startingcompounds are prepared by treating each of the following progesteroneswith ethyl orthoformate with ethanol in the presence ofp-toluene-sulphonic acid according to known procedures:

16u-methyl-4-pregnene-3,20-dione, l6B-methyl-4-pregnene-3,20-dione,16u-rnethyl-l7a-acetoxy-4-pregnene-3,20-dione,16B-methyl-17ot-acetoxy-4-pregnene-3,20-dione,16-methylene-17ot-propionyloxy-4-pregnene-3,20-dione,

and l6-methylene-l7a-caproyloxy-4-pregnene-3,20-dione.

The following enol-ethyl ethers are thereby formed utilizing knowntechniques:

3-ethoxy-1 6a-methyl-3 ,5 -pregnadien-20-one,

3-ethoxy- 1 6p3-methyl-3 ,5 -pregnadien-20-one,

3-ethoxyl 6a-rnethyl L-3C6lOXy-3 ,S-pregnadien-ZO-one,

3-ethoxy-16,8-methyl-17a-acetoxy-3,S-pregnadien-ZO-one,

3-ethoxy-16-methylene-l7ot-propionyloxy-3,5-pregnadien- 20-one, and

3-ethoxylfi-methylene-17a-caproyloxy-3,5-pregnadien- 20-one.

In a manner similar to that described in Example 1A, treat each of theabove 3-ethoxy-3,5-pregnadien-20-ones with a solution of phosphorusoxychloride in dimethylformamide followed by treating the reactionmixture with aqueous potassium acetate. Isolate and purify the resultautproducts in a manner similar to that described in Example 1A to obtainthe following respective 6-formyl derivatives:

3-ethoxy-6-formyl-16a-methyl-3,5-pregnadien-20-one,

3-ethoxy-6-formyl-16B-methyl-3,5-pregnadien-20-one,

3-ethoxy-6-formyl-16a-methyl-17a-acetoxy-3,5-pregnadien-ZO-one,

3 -ethoxy-6-formyll GB-methyl- 1 7aacetoxy-3 ,5 -pregnadien-ZO-one,

3-ethoxy-6-formyl-16-methylene-l7u-propionyloxy-3 ,5-

pregnadien-ZO-one, and

3-ethoxy-6-formyl-l6-methylene-17a-caproyloxy-3,5-

pregnadien-20-one.

(B) 3-ethoxy 6 oximinomethyl-3,S-pregnadien-ZO- ones.In a manner similarto that described in Example 1B, treat each of the 3-ethoxy-6-formylderivatives prepared as described in Example 5A hereinabove withhydroxylamine hydrochloride in aqueous ethanol together with sodiumacetate. Isolate and purify the resultant respective products in amanner similar to that described in Example 1B to obtain the followingrespective 3-ethoxy-6-oximinomethyl derivatives:

3-ethoXy-6-oximinomethyll 6u-methyl-3 ,5 -pregnadien- 20-one,

3-ethoxy-6-oximinomethyl-16fi-methy1-3,5-pregnadien- 20-one,

3-ethoxy-6-oximinomethyllfiu-methyll7a-acetoxy-3,5-

pregnadien-ZO-one,

3-ethoxy-6-oximinomethyl-165-methyl-17u-acetoxy-3,5-

pregnadien-ZO-one,

3-ethoxy-6-oximinomethyl-l6-methylene-17a-propionyloxy-3,S-pregnadien-ZO-one,and

3-ethoxy-6-oximinomethyl-l6-methylene-l7u-caproyloxy-3,5-pregnadien-20-one.

(C) 6-oximinomethyl-4,6-pregnadiene-3,20-diones.-In a manner similar tothat described in Example 1C, treat each of the 3-ethoxy-6-oximinomethylderivatives prepared in above Example 5B with 2,3-dichloro-'5,6-dicyano-1,4-benzoquinone in aqueous acetone at 207 C. Isolate and purify theresultant respective products in a manner similar to that described inExample 1C to obtain the following6-oximinomethyl-4,6-pregnadiene-3,ZO-diones:

6-oximinomethyl-lGot-methyl-4,6-pregnadiene-3,20-dione,

6-oximinomethyl-16,B-methyl-4,6-pregnadiene-3,ZO-dione,

6-oximinomethyl-1a-methyl-l7a-acetoxy-4,6-pregnadiene-3,20-dione,

6-oximinomethyl-16fl-methyl-17u-acetoxy-4,6-pregnadiene-3,20-dione,

6-oximinomethyl-l 6-methylenel7a-propionyloxy-4,6-

pregnadiene-3,20-dione, and

6-oximin0methyl-16-methylene-17u-caproyloxy-4,6-pregnadiene-3,2 -dione.

(D) 6-cyano-4,6-pregnadiene-3,20-diones.-In a manner similar to thatdescribed in Example 2A, treat each of the6-oximinomethyl-4,6-pregnadienes prepared in above Example C withphosphorus oxychloride in pyridine in an atmosphere of nitrogen at atemperature of about C. Isolate and purify the resultant respectiveproducts in a manner similar to that described in Example 2A to obtainthe following respective products to obtain6-cyano-4,6-pregnadiene-3,20-diones:

6-cyanol 6a-methyl-4,G-pregnadiene-3,20-dione,

fi-cyano-l 65-methyl-4,6-pregnadiene-3,20'-dione,

6-cyano-16a-methyl-l7a-acetoxy-4,6-pregnadiene-3,20-

dione,

6-cyano-16fl-methy1-l7a-acetoxy-4, 6-pregnadiene-3,20-

dione,

6-cyano-l 6-methylene17a-propionyloxy-4,G-pregnadiene- 3,20-dione, and

6 -cyano-1 6-methylenel7a-caproyloxy-4, 6-pregnadiene- 3,20dione.

10 EXAMPLE 6 Alternate preparation of 6-cyano-16-methylene-17a-acetoxy-4,6-pregnadiene-3,20-dione Add 1 g. of6-oximinomethyl-l6-methylene-17a-acetoxy- 4,6-pregnadiene-3,20-dione to25 ml. of acetic anhydride and mgm. of sodium acetate. Heat the reactionmixture at reflux temperature for three hours; then cool, pour into alarge volume of water and stir the reaction mixture for about an hour.Filter and air dry the resultant precipitate via chromatographictechniques in a manner similar to that described in Example 2C to obtain6- cyano-16-methylene-17a-acetoxy 4,6 pregnadiene-3,20- dione.

We claim:

11. A compound having the following structural formu a:

=0 CH3 L W CHsi i ]H=NOR wherein R is a member selected from the groupconsisting of hydrogen and lower alkanoyl; W is a member selected fromthe group consisting of hydrogen, methylene, (H,umethyl) and(H,fl-methyl); and Y is a member selected from the groupconsisting oflower alkanoyloxy, and hydrogen when W is hydrogen or (=H,methyl).

2. A compound according to claim 1 wherein R is hydrogen and Y is loweralkanoyloxy.

3. A compound according to claim 1 wherein R is hydrogen, Y is loweralkanoyloxy and W is methylene, said compound being6-oximinomethyl-l6-methylenie- 17u-loweralkanoyloxy-4,6-pregnadiene-3,20-dione.

4. A compound according to claim 1 wherein R is hydrogen, Y is acetoxy,and W is methylene, said compound being6-oximinomethyl-l6-methy1ene-17u-acetoxy- 4,6-pregnadieue-3,20=dione.

5. A compound according to claim 1 wherein R and Y are acetoxy and W ismethylene, said compound being 6-acetoximinomethyl-16-methylene 17aacetoxy-4,6 pregnadiene-3,20-dione.

6. A process for the preparation of a compound having the followingstructural Formula I:

wherein W is a member selected from the group consisting of hydrogen,methylene, (H -methyl), and (Hus-methyl); and Y is a member selectedfrom the group consisting of lower alkanoyloxy, and hydrogen when W ishydrogen 1 1 or (H,rnethyl); which comprises treating a 6-oximinomethylsteroid of following structural Formula II:

I CH=NOH (11 drating agent is phosphorus oxychloride, said processcomprising treating 6-oximinomethyl-16-methylene17u-loweralkanoyloxy-4,6-pregnadiene-3,20-dione with phosphorus oxychloride,whereby is formed 6-cyano-16-methylene- 17u-1OWCI'alkanoyloxy-4,6-pregnadiene-3,ZO-dione.

8. Process of claim 7 wherein Y is acetoxy, said process comprisingtreating6-oximinomethyl-16-methylene-17aacetoxy-4,6-pregnadiene-3,20-dione withphosphorus oxychloride whereby is formed6-cyano-16-methylene-17aactoxy-4,6-pregnadiene-3,2 0 dione.

References Cited UNITED STATES PATENTS 3,019,240 1/1962 Bowers et al.260397.3 3,046,285 7/ 1962 Bowers et a1 260397.45 3,311,617 3/1967Petrow et a1 260-239.55 3,527,778 9/1970 Baran et al. 260--397.45

HENRY A. FRENCH, Primary Examiner US. Cl. X.R. 260-3973, 999

